Axl is a member of the TAM (Tyro3, Axl, and Mer) family of receptor tyrosine kinases (O'Bryan et al, 1991; Lai et al, 1991). It was originally identified as a transforming gene in hematological malignancies (O'Bryan et al, 1991; Janssen et al, 1991). Dysregulation of Axl or its ligand Gas6 is implicated in the pathogenesis of a variety of human cancers. Axl overexpression has been reported in a wide array of human cancers (Berclaz et al, 2001; Craven et al, 1995; Shieh et al, 2005; Sun et al, 2004; Ito et al, 1999) and is associated with invasiveness and metastasis in lung (Shieh et al, 2005), prostate (Sainaghi et al, 2005), breast (Meric et al, 2002; Zhang et al, 2008), gastric (Wu et al, 2002), and pancreatic (Koorstra et al, 2009) cancers, renal cell carcinoma (Chung et al, 2003), as well as glioblastoma (Hutterer et al, 2008). Recently, by profiling of phosphotyrosine signaling, activated Axl protein was detected in about 5% primary tumors of NSCLC (Rikova et al, 2007). Axl expression is induced by targeted and chemotherapy drugs and drug-induced Axl expression confers resistance to chemotherapy in acute myeloid leukemia (Hong et al, 2008), as well as resistance to imatinib and Lapatinib/Herceptin in gastrointestinal stromal tumors (Mehadevan, et al, 2007) and breast cancer (Liu et al, 2009), respectively. Other publications relating to Axl and anti-Axl antibodies include WO2004/039955, WO2009/063965; co-owned U.S. application No. 61/228,915 filed Jul. 27, 2009; WO2009/062690; WO2004/008147; U.S. Pat. No. 5,468,634.
It is clear that there continues to be a need for agents that have clinical attributes that are optimal for development as therapeutic agents. The invention described herein meets this need and provides other benefits.
All references cited herein, including patent applications and publications, are incorporated by reference in their entirety.